Macrophages possess a number of mechanisms to regulate the balance between cholesterol[unreadable] uptake/synthesis and export. Of major importance are transport mechanisms that promote the efflux of[unreadable] excess cholesterol to extracellular acceptors. The removal of excess cholesterol is critical in the vessel wall,[unreadable] where macrophage uptake of lipoprotein-derived lipid can lead to a pathological cholesterol load in the[unreadable] absence of sufficient removal systems. Two members of the ATP binding cassette (ABC) superfamily of[unreadable] transmembrane transporters, ABCA1 and ABCG1, play critical roles in preventing cholesterol lipid[unreadable] accumulation in macrophages. Extensive studies have shown that ABCA1 promotes efflux of both[unreadable] cholesterol and phospholipids to lipid-poor apolipoproteins, in particular, apoA-l. In contrast, ABCG1 appears[unreadable] to promote efflux by redistributing intracellular cholesterol to plasma membrane domains accessible for[unreadable] removal by HDL, but not lipid-poor apoA-l. Thus, factors that affect the lipidated state of apoA-l may[unreadable] modulate the activity of these two transporters. During inflammation, HDL undergoes extensive remodeling[unreadable] that leads to the generation of particles that are significantly altered in size, charge, and apolipoprotein and[unreadable] lipid content. These alterations are primarily brought about by the acute phase reactants serum amyloid A[unreadable] (SAA) and Group IIA secretory phospholipase A2. Accumulating evidence from multiple laboratories,[unreadable] including ours, has established that SAA, either delivered as acute phase HDL or in a lipid-free form, can[unreadable] enhance macrophage cholesterol efflux. In Preliminary Data, we provide evidence that in the presence of[unreadable] cholesterol ester transfer protein, phospholipid depletion of HDL particles by Group IIA sPLA2 can lead to the[unreadable] generation of small, lipid-depleted HDL particles. We aim to show that a major consequence of the acute[unreadable] phase response is an increase in the mobilization of cholesterol from the periphery, and an accelerated rate[unreadable] of macrophage reverse cholesterol transport. We hypothesize that SAA and sPLA2 promote macrophage[unreadable] lipid efflux by modifying HDL acceptors and through direct interactions with macrophage cells. To test this[unreadable] hypothesis, we propose the following Specific Aims: 1) To demonstrate that inflammation-induced[unreadable] remodeling of HDL generates substrates that enhance ABCA1 and ABCG1-dependent efflux; 2) To[unreadable] investigate the mechanism(s) by which SAA and sPLA2 promote macrophage cholesterol efflux; and 3) To[unreadable] test the hypothesis that SAA protects against atherosclerotic lipid accumulation through an ABCA1 and/or[unreadable] ABCG1 -dependent mechanism.